Objective To analyze time trends in incidence, causes and risk factors for traumatic spinal cord injuries (TSCI) in Estonia between 1997-2007 and 2008-2018. Design Retrospective, population-based cohort study. Setting Specialized trauma centres in Estonia. Participants Medical records of patients with TSCI from 1997 to 2018. Intervention None. Outcome measures Demographical data, crude and age- and sex-adjusted incidence rates, causes of TSCI, level and extent of injury, associated injuries. Results A total of 940 new patients with TSCI were identified for the period of 1997-2018. The average annual incidence rate (standardized to the Estonian population by age and sex in 2011) decreased significantly from 37.8 (95% confidence interval (CI) 34.6-41.1) in the first period (1997-2008) to 28.2 per million population (95% CI 25.3-31.0) during the second period (2008-2018) (incidence rate ratio 0.74 (95% CI 0.65-0.85), P < 0.0001). The decrease in incidence was most significant among young men. The mean age at injury increased from 38.7 (+/- 16.7) years to 46.6 (+/- 19.9) years, P < 0.0001. Falls were the leading cause of injury during both periods followed by traffic accidents and sports injuries. Still, traffic accidents as a cause of TSCI decreased significantly (from 30.5% to 20.6%, P = 0.001) and falls increased (from 39.9% to 59.5%, P < 0.0001) during the second period. Alcohol consumption prior to injury also decreased significantly from 66.0% to 55.1% (P = 0.006). Conclusion Estonia has become closer to other European countries regarding TSCI during the last decade; TSCI incidence has significantly decreased, the mean age at injury and the percentage of falls have increased.

Extracellular matrix in solid tumors has emerged as a specific, stable, and abundant target for affinity-guided delivery of anticancer drugs. Here we describe the homing peptide that interacts with the C-isoform of Tenascin-C (TNC-C) upregulated in malignant tissues. TNC-C binding PL3 peptide (amino acid sequence: AGRGRLVR) was identified by in vitro biopanning on recombinant TNC-C. Besides TNC-C, PL3 interacts via its C-end Rule (CendR) motif with cell-and tissue penetration receptor neuropilin-1 (NRP-1). Functionalization of iron oxide nanoworms (NWs) and metallic silver nanoparticles (AgNPs) with PL3 peptide increased tropism of systemic nanoparticles towards glioblastoma (GBM) and prostate carcinoma xenograft lesions in nude mice (eight and five-fold respectively). Treatment of glioma-bearing mice with proapoptotic PL3-guided NWs improved the survival of the mice, whereas treatment with untargeted particles had no effect. PL3-coated nanoparticles were found to accumulate in TNC-C and NRP-1-positive areas in clinical tumor samples, suggesting a translational relevance. The systemic tumor-targeting properties and binding of PL3-NPs to the clinical tumor sections, suggest that the PL3 peptide may have applications as a targeting moiety for the selective delivery of imaging and therapeutic agents to solid tumors.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or Covid-19), which began as an epidemic in China and spread globally as a pandemic, has necessitated resource management to meet emergency needs of Covid-19 patients and other emergent cases. We have conducted a survey to analyze caseload and measures to adapt indications for a perception of crisis. Methods We constructed a questionnaire to survey a snapshot of neurosurgical activity, resources, and indications during 1 week with usual activity in December 2019 and 1 week during SARS-CoV-2 pandemic in March 2020. The questionnaire was sent to 34 neurosurgical departments in Europe; 25 departments returned responses within 5 days. Results We found unexpectedly large differences in resources and indications already before the pandemic. Differences were also large in how much practice and resources changed during the pandemic. Neurosurgical beds and neuro-intensive care beds were significantly decreased from December 2019 to March 2020. The utilization of resources decreased via less demand for care of brain injuries and subarachnoid hemorrhage, postponing surgery and changed surgical indications as a method of rationing resources. Twenty departments (80%) reduced activity extensively, and the same proportion stated that they were no longer able to provide care according to legitimate medical needs. Conclusion Neurosurgical centers responded swiftly and effectively to a sudden decrease of neurosurgical capacity due to relocation of resources to pandemic care. The pandemic led to rationing of neurosurgical care in 80% of responding centers. We saw a relation between resources before the pandemic and ability to uphold neurosurgical services. The observation of extensive differences of available beds provided an opportunity to show how resources that had been restricted already under normal conditions translated to rationing of care that may not be acceptable to the public of seemingly affluent European countries.

Background Emotional health disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) and their causes are largely unexplored. Corticotropin-releasing hormone receptor 1 (CRHR1) is a key factor in stress reactivity and development of mental health disturbances after adverse life-events. Methods We explore the effect of CRHR1 genotype on mental health after aSAH in a retrospective cohort study. One hundred twenty-five patients have been assessed using EST-Q mental health questionnaire. Genotyping of CRHR1 single nucleotide polymorphisms (SNP-s) was performed (Rs7209436, Rs110402, Rs242924). Results Fatigue was present in almost half of aSAH patients, depression and anxiety in one-third. There was a high prevalence of insomnia and panic complaints. Rs110402 minor allele decreased the risk of depression (OR = 0.25, p = 0.027 for homozygotes). Depression was present in 14% vs 41% in minor and major allele homozygotes, respectively. Rs110402, Rs242924 and Rs7209436 minor alleles and TAT-haplotype, formed by them, were protective against fatigue. After Bonferroni correction only the association of Rs110402 with fatigue remained statistically significant (OR = 0.21, p = 0.006 for minor allele homozygotes). Results remained statistically significant when adjusted for gender, admission state, age and time from aSAH. In multiple regression analysis occurrence of fatigue was dependent on anxiety, modified Rankin score and Rs110402 genotype (R 2 = 0.34, p < 0.001). Conclusions CRHR1 minor genotype was associated with a lower risk of fatigue and depression after aSAH. Genetic predisposition to mental health disturbances associated with negative life-events could be a risk factor for fatigue and depression after aSAH and selected patients might benefit from advanced counselling in the recovery phase.

Quality of life (QoL) disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) both in physical and mental health domains and their causes are not clearly understood. Corticotropin-releasing hormone receptor 1 (CRHR1) is involved in stress reactivity and development of mental health disturbances after negative life-events. We performed a retrospective cohort study of long-term QoL outcomes among 125 surgically treated aSAH patients (2001–2013). QoL was assessed with Short Form Health Survey (SF-36) and compared to an age and gender matched general population. Genotyping of CRHR1 single nucleotide polymorphisms was performed (Rs7209436, Rs110402, Rs242924) and their effect on QoL scores was explored. aSAH patients experienced a reduced quality of life in all domains. CRHR1 minor genotype was associated with higher SF-36 mental health (OR = 1.31–1.6, p < 0.05), role-emotional (OR = 1.57, p = 0.04) and vitality scores (OR = 1.31–1.38, p < 0.05). Association of all studied SNP’s with vitality and Rs242924 with mental health scores remained statistically significant after Bonferroni correction. Mental quality of life scores were associated with physical state of patients, antidepressant history and CRHR1 genotype. Predisposition to mental health disturbances after stressful life-events might be associated with reduced mental QoL after aSAH and selected patients could be provided advanced counselling in the recovery phase.

OBJECTIVES:To evaluate impact of first therapy session, containing functional electrical stimulation (FES) and therapeutic exercises (TE) on erector spinae (ES) and rectus abdominis (RA) force generation in persons with spinal cord injury (SCI).METHODS:Five men with SCI were divided in two groups - FES+TE received concurrent FES on ES and RA and TE, TE only TE. Participants performed exercises for improving sitting balance and posture. Muscles' electrical activity was evaluated by electromyography; amplitude (AEMG) and median frequency (MF) were used for analysis.RESULTS:AEMG of ES left (L) increased 292.9% (g=-0.92), right (R) 175% (g=-1.01), RA L 314.3% (g=-0,81, P<0.05), R 266.7% (g=-0.08) in FES+TE. AEMG of ES L increased 47.6% (g=-0.46), R 96.4% (g=-0.95); RA L 7.1% (g=-0.97), but R decreased 6.7% (g=0.12) in TE. MF of ES L increased 108.5% (g=-0.74), R 184% (g=-1.25); RA L 886.7% (g=3-05, P<0.05), R 817.6% (g=-2.55, P<0.05) in FES+TE. MF of ES L increased 95.2% (g=-1.02), R 161.4% (g=-1.64); RA L 3,2% (g=-0.06), R 30.8% (g=-0.46) in TE.CONCLUSIONS:In SCI persons, single session exercises and concurrent functional electrical stimulation may be more effective on muscles` force generation than only exercises. However, replication of the results is needed before clinical implementation.

Tumor-selective drug conjugates can potentially improve the prognosis for patients affected by glioblastoma (GBM) - the most common and malignant type of brain cancer with no effective cure. Here we evaluated a novel tumor penetrating peptide that targets cell surface p32, LinTT1 (AKRGARSTA), as a GBM targeting ligand for systemically-administered nanoparticles. LinTT1-functionalization increased tumor homing of iron oxide nanoworms (NWs) across a panel of five GBM models ranging from infiltratively-disseminating to angiogenic phenotypes. LinTT1-NWs homed to CD31-positive tumor blood vessels, including to transdifferentiated endothelial cells, and showed co-localization with tumor macrophages and lymphatic vessels. LinTT1 functionalization also resulted in increased GBM delivery of other types of systemically-administered nanoparticles: silver nanoparticles and albumin-paclitaxel nanoparticles. Finally, LinTT1-guided proapoptotic NWs exerted strong anti-glioma activity in two models of GBM, including doubling the lifespan of the mice in an aggressive orthotopic stem cell-like GBM that recapitulates the histological hallmarks of human GBM. Our study suggests that LinTT1 targeting strategy can be used to increase GBM uptake of systemic nanoparticles for improved imaging and therapy.

Oncofetal fibronectin (FN-EDB) and tenascin-C C domain (TNC-C) are nearly absent in extracellular matrix of normal adult tissues but upregulated in malignant tissues. Both FN-EDB and TNC-C are developed as targets of antibody-based therapies. Here we used peptide phage biopanning to identify a novel targeting peptide (PL1, sequence: PPRRGLIKLKTS) that interacts with both FN-EDB and TNC-C. Systemic PL1-functionalized model nanoscale payloads [iron oxide nanoworms (NWs) and metallic silver nanoparticles] homed to glioblastoma (GBM) and prostate carcinoma xenografts, and to non-malignant angiogenic neovessels induced by VEGF-overexpression. Antibody blockage experiments demonstrated that PL1 tumor homing involved interactions with both receptor proteins. Treatment of GBM mice with PL1-targeted model therapeutic nanocarrier (NWs loaded with a proapoptotic peptide) resulted in reduced tumor growth and increased survival, whereas treatment with untargeted particles had no effect. PL1 peptide may have applications as an affinity ligand for delivery of diagnostic and therapeutic compounds to microenvironment of solid tumors.

Background: Patients with Parkinson's disease can show brief normalization of motor activity in response to intense external stimuli a phenomenon known as paradoxical kinesis. The purpose of the present study was to examine the effect of alarming auditory signals on the level of viscoelastic stiffness of skeletal muscles as an indicator of parkinsonian rigidity. Methods: Myotonometry was used to determine the changes of viscoelastic stiffness of skeletal muscles in ten patients in an advanced stage of Parkinson's disease, treated with deep brain stimulation, and ten healthy controls. The measurements were repeated and compared during the stimulation-on and stimulation-off periods, with and without auditory alarming signals. Findings: The mean values of stiffness measured in the stimulation-off phase (370.4 N/m) were significantly higher than the values obtained in the stimulation-on phase (339.2 N/m) (q = 6.05; P < 0.01) but also in the stimulation-off with alarming signals phase (349.6 N/m) (q = 4.04; P < 0.05). In the normal controls, exposure to the auditory alarming signals did not change the values of viscoelastic stiffness. Interpretation: These findings demonstrate that the phenomenon of paradoxical kinesis is associated with the changes of muscular rigidity in parkinsonian patients. Results from the study may help to establish new strategies for addressing motor disabilities in patients with Parkinson's disease.

Substantia nigra (SN) hyper-echogenicity (SN+) describes an enlargement (>90th percentile) of the area of echogenicity at the anatomic site of the SN in the midbrain detected by transcranial sonography. This ultrasound sign has proven to be a valuable marker supporting the clinical diagnosis of Parkinson's disease (PD). Although there is considerable variation in the extent of echogenic signals at the anatomic site of the SN among PD patients, previous work suggests that SN+ is a stable marker throughout the course of the disease. The present study focused on two aspects: (i) determining whether SN+ values differ between the sides, mirroring the asymmetric character of the disease; and (ii) determining whether age has an influence on SN echogenicity. This cross-sectional study included 300 PD patients and 200 healthy controls. SN+ was measured planimetrically by transcranial sonography. Echogenicity was analyzed separately for onset and non-onset sides, with onset side defined as the SN contralateral to the side of the body that first manifested PD-related motor impairment. Age of the patients and healthy controls at study time was used for correlation. We found that the onset SN+ contralateral to the side of initial motor symptoms was on average 17.6% larger than its counterpart. However, we also found that contrary to the control group, where an increase in age was associated with an increase in size of SN+, age of PD patients was associated with a decline in size of the onset SN+. Furthermore, SN measured at the onset side of PD patients correlated significantly with patient age and Hoehn and Yahr stage, a scale that grades PD severity, although this was not the case for the non-onset side. The present study indicates that changes in SN echogenicity have a different dynamic depending on the onset side of the disease. The age at study time had a significantly negative effect on the size of onset SN+, the effect on the non-onset side was non-significant. We conclude that for appropriate PD analysis, onset SN+ is a more important marker than the average of both sides of SN. Furthermore, we found that among healthy controls, the size of SN+ increases with age.

Background and objectives: Functional electrical stimulation (FES) has shown good results in improving static and dynamic sitting balance in persons with spinal cord injuries. There is limited information about how regular surface FES combined with therapeutic exercise (TE) affect dynamic sitting balance and muscle tone. The objective of this study was to evaluate the effectiveness of a six-week physical therapy program consisting of FES and TE on muscle tone and sitting balance in persons with spinal cord injury (SCI). It was also important to explore the relationship between muscle tone and dynamic sitting balance. The third objective was to assess the change of characteristics over a six month period, when no intervention was carried out. Material and methods: Five men with SCI were alternately allocated to two study groups: SCI_FES+TE and SCI_TE. Eight healthy control group participants were recruited to collect reference data. SCI participants' intervention lasted for six weeks in their homes. SCI_FES+TE conducted exercises with FES applied on erector spinae (ES) and rectus abdominis (RA) muscles. SCI_TE conducted exercises only. Muscle oscillation frequency (MOF; characterizing muscle tone) and limits of stability (LOS; characterizing sitting balance) were measured. A crossover study design was used. The time between the initial intervention and the crossover was seven months (ClinicalTrials registration ID NCT03517787). Results: MOF in SCI_FES+TE increased by 6.0% for ES and 6.1% for RA muscles. LOS of flexion increased 30.1% in SCI_FES+TE. Increase in lateral directions was similar for both study groups. Moderate to high negative correlation was found between MOF and LOS. After seven months, MOF of ES decreased 0.8%, MOF or RA decreased 1.4%, LOS of flexion decreased 31.9%, and LOS of lateral flexion to the left decreased 46.4%. Conclusions: The six-week therapy program combining FES and TE increased trunk muscle tone and dynamic sitting balance in flexion more than TE alone. Higher antagonist muscle tone negatively affects dynamic sitting balance and center of pressure (COP) trajectory distance in various directions. After seven months, a slight decline in trunk muscles tone values and an extensive decrease in sitting balance values were noticed.

Background: There is lack of data on the incidence of Parkinson's disease (PD) based on repeat studies. Mortality rates of PD in Estonia have never been studied before. Objectives: To estimate the incidence and mortality rates of PD in -Estonia, to compare current incidence rates with those of the prior epidemiological study in Estonia, and to examine the reported causes of death of the study population. Methods: Eligible subjects were identified from multiple case-finding sources. Subjects were subsequently tracked on the Electronic-Health Record until either the end of the study, or their death. Incidence rates and standardized mortality ratios (SMR) were calculated. Causes of death were identified, based on the data from death certificates. Results: In the current study, the overall age-adjusted incidence rate was 28.0/100,000 person-years (95% CI 25.2-30.8). Compared with the previous study, the age-adjusted incidence rate inEstonia has not significantly changed (rate ratio 1.11; p = 0.19). Overall SMR for the inception cohort of PD cases with a median follow-up time of 5 years was 1.12 (95% CI 0.88-1.36; p = 0.3). For those deceased subjects known to have had clinically diagnosed PD, this was mentioned on 46.8% of death certificates. Conclusions: Over the last 20 years, the overall incidence of PD in Estonia has remained comparatively stable. The data did not show an excess mortality in PD patients (vs. general population) in the first 5 years of the disease.

Acta Neurologica ScandinavicaVolume 138, Issue 3 p. 266-266 LETTER TO THE EDITOR Response to the letter by Scorza et al L. Kadastik-Eerme, L. Kadastik-Eerme liiskadastikeerme@gmail.com orcid.org/0000-0002-9788-9402 Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this authorN. Taba, N. Taba Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, EstoniaSearch for more papers by this authorT. Asser, T. Asser Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this authorP. Taba, P. Taba Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this author L. Kadastik-Eerme, L. Kadastik-Eerme liiskadastikeerme@gmail.com orcid.org/0000-0002-9788-9402 Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this authorN. Taba, N. Taba Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, EstoniaSearch for more papers by this authorT. Asser, T. Asser Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this authorP. Taba, P. Taba Department of Neurology and Neurosurgery, University of Tartu, Tartu, EstoniaSearch for more papers by this author First published: 21 June 2018 https://doi.org/10.1111/ane.12970Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume138, Issue3September 2018Pages 266-266 RelatedInformation

A previous epidemiological study of Parkinson's disease (PD) in the county of Tartu, Estonia, found an adjusted prevalence rate of 152/100 000 persons. We aimed to determine PD prevalence almost 20 years later, as well as evaluate any dynamic changes in disease frequency compared to the first study.

Background: Myotonometric evaluation of viscoelastic stiffness of skeletal muscles has been proposed to document the effect of surgical or pharmacological treatment on rigidity in patients with Parkinson's disease. The aim of the study was to analyze the changes of viscoelastic stiffness induced by deep brain stimulation.Methods: Fifteen patients in an advanced stage of Parkinson's disease participated in the study. The study took place in the off-medication conditions after one night of drug withdrawal. The Unified. Parkinson's Disease Rating Scale was used for clinical assessment of the disease. Myotonometry was used to measure viscoelastic stiffness in the resting muscles before and directly after passive wrist movements, commonly used for clinical evaluation of rigidity. The measurements were repeated during the stimulation-on and stimulation-off periods and compared with fifteen healthy control persons.Findings: The clinical scores for wrist rigidity improved from 3.0 (1-4) to 0.93 (0-2) (P< 0.05) due to brain stimulation. The mean values of viscoelastic stiffness were similar before and after passive wrist movements, but the differences between the patients with high vs. low rigidity values (354.9 vs 310.2 N/m; P< 0.05) and in stimulation-off vs. stimulation-on conditions (342.7 vs 310.5 N/m; P < 0.05) were significant only if the measurements had been performed after passive wrist movements.Interpretation: Effective deep brain stimulation and increased rigidity can significantly change viscoelastic stiffness in the resting muscles in patients with Parkinson's disease, especially if evaluated after passive wrist movements. This paper supports the use of myotonometry for objective quantification of parkinsonian rigidity at rest. (C) 2017 Elsevier Ltd. All rights reserved.

Glioblastoma (GB) is the most angiogenic tumor. Nevertheless, antiangiogenic therapy has not shown significant clinical efficacy. The aim of this study was to assess blood vessel characteristics on survival of GB patients. Surgically excised GB tissues were histologically examined for overall proportion of glomeruloid microvascular proliferation (MP) and the total number of blood vessels. Also, immunohistochemical vascular staining intensities of CD133 and ICAM-1 were determined. Vessel parameters were correlated with patients' overall survival. The survival time depended on the number of blood vessels (p = 0.03) but not on the proportion of MP. Median survival times for patients with low (<median) and high (≥median) number of blood vessels were 9.0 months (95% CI: 7.5–10.5) and 12.0 months (95% CI: 9.3–14.7). Also, median survival times for patients with low (<median) and high (≥median) vascular expression level of CD133 were 9.0 months (95% CI: 8.0–10.1) and 12.0 months (95% CI: 10.3–13.7). In contrast, the staining intensity of vascular ICAM-1 did not affect survival. In multivariate analysis, the number of blood vessels emerged as an independent predictor for longer overall survival (HR: 2.4, 95% CI: 1.2–5.0, p = 0.02). For success in antiangiogenic therapy, better understanding about tumor vasculature biology is needed.